دورية أكاديمية
أعرض في EDS

ALS/FTD mutations in UBQLN2 are linked to mitochondrial dysfunction through loss-of-function in mitochondrial protein import.

التفاصيل البيبلوغرافية
العنوان: ALS/FTD mutations in UBQLN2 are linked to mitochondrial dysfunction through loss-of-function in mitochondrial protein import.
المؤلفون: Lin BC; Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Phung TH; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Higgins NR; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Greenslade JE; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Prado MA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Finley D; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Karbowski M; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Polster BM; Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Monteiro MJ; Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
المصدر: Human molecular genetics [Hum Mol Genet] 2021 Jun 17; Vol. 30 (13), pp. 1230-1246.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
مواضيع طبية MeSH: Mutation*, Adaptor Proteins, Signal Transducing/*genetics , Amyotrophic Lateral Sclerosis/*genetics , Autophagy-Related Proteins/*genetics , Frontotemporal Dementia/*genetics , Mitochondria/*genetics , Mitochondrial Proteins/*genetics, Animals ; Cell Line ; Disease Models, Animal ; HeLa Cells ; Humans ; Immunoblotting ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microscopy, Electron, Transmission ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mitochondrial Proteins/metabolism ; Oxygen Consumption/genetics ; Proteomics/methods ; Mice
مستخلص: UBQLN2 mutations cause amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), but the pathogenic mechanisms by which they cause disease remain unclear. Proteomic profiling identified 'mitochondrial proteins' as comprising the largest category of protein changes in the spinal cord (SC) of the P497S UBQLN2 mouse model of ALS/FTD. Immunoblots confirmed P497S animals have global changes in proteins predictive of a severe decline in mitochondrial health, including oxidative phosphorylation (OXPHOS), mitochondrial protein import and network dynamics. Functional studies confirmed mitochondria purified from the SC of P497S animals have age-dependent decline in nearly all steps of OXPHOS. Mitochondria cristae deformities were evident in spinal motor neurons of aged P497S animals. Knockout (KO) of UBQLN2 in HeLa cells resulted in changes in mitochondrial proteins and OXPHOS activity similar to those seen in the SC. KO of UBQLN2 also compromised targeting and processing of the mitochondrial import factor, TIMM44, resulting in accumulation in abnormal foci. The functional OXPHOS deficits and TIMM44-targeting defects were rescued by reexpression of WT UBQLN2 but not by ALS/FTD mutant UBQLN2 proteins. In vitro binding assays revealed ALS/FTD mutant UBQLN2 proteins bind weaker with TIMM44 than WT UBQLN2 protein, suggesting that the loss of UBQLN2 binding may underlie the import and/or delivery defect of TIMM44 to mitochondria. Our studies indicate a potential key pathogenic disturbance in mitochondrial health caused by UBQLN2 mutations.
(© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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معلومات مُعتمدة: R01 GM129584 United States GM NIGMS NIH HHS; R01 NS098243 United States NS NINDS NIH HHS; R01 NS100008 United States NS NINDS NIH HHS; RF1 NS098243 United States NS NINDS NIH HHS
المشرفين على المادة: 0 (Adaptor Proteins, Signal Transducing)
0 (Autophagy-Related Proteins)
0 (Mitochondrial Proteins)
0 (UBQLN2 protein, human)
تواريخ الأحداث: Date Created: 20210423 Date Completed: 20220328 Latest Revision: 20240226
رمز التحديث: 20240226
مُعرف محوري في PubMed: PMC8212775
DOI: 10.1093/hmg/ddab116
PMID: 33891006
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2083
DOI:10.1093/hmg/ddab116